Men and other animals are continually exposed to infection and re-infection by various species and strains of free-living limax amoebae which can be detected in the faeces, nasopharynx and bronchi. In all parts of the world they form part of the environment. Experimentally in animals they induce changes like those of collagen and auto-immune diseases and are characterized by vasculitis, myosotis, hepatitis, pyelitis and splenomegaly. They can often be seen in the tissues of animals. Such animals show lymphadenopathy with an appearance like that of human Hodgkin's disease or a state like that of advanced malignant disease. These organisms may also be recovered from all the tissues of cases of collagen and auto-immune diseases and from human and many animal tumors and may also occur in the tissues of apparently healthy individuals. They cannot be identified in ordinary histological sections, but can be demonstrated by immunofluorescent methods.
The definite cause of rheumatoid arthritis is presently unknown. Rheumatoid arthritis is a crippling disease, characterized by the inflammation of several joints of the body, with swelling, pain and stiffness. Rheumatoid arthritis is a disorder that afflicts about fifteen million people in the Western World alone. Successful early treatment may avert the destructive, deforming phase of the disease. Therapy has been directed largely at non-specific suppression of inflammatory and immunologic processes. Asprin is the cornerstone of therapy for rheumatoid arthritis and can reduce synovial inflammation, improve function and reduce pain in a majority of patients in view of its analgesic action. Widespread interest in rheumatoid arthritis arose when Hench (1949) introduced the use of cortisone in treatment. Chemical compounds which have been commonly used in treating rheumatoid arthritis are corticosteroids, gold salts, antimalarial drugs, immunosuppressive agents and a whole range of so-called non-steroidal drugs, e.g. indomethacin, phenylbutazones, anthranilic acid, benzathiazine derivatives, phenylacetic acid (Ibuprofen), propionic acid (Naproxen) and D-penicillamine. Most of these drugs bring temporary relief to the arthritic patient but present the danger of side effects and the physician has to balance the potential benefit against the risks. However, arthritis reoccurs following withdrawal of such chemical treatment. For many years rheumatoid arthritis was considered to be an infection (Hollander et al., 1960; Robinson, 1967), but with the advent of the concept of auto-immunity this idea lost favor. Such a view has recently been revived (Lancet, 1970, 2, 303) and is supported by many observations. It is highly likely that the limax amoebae, found in all the collagen and auto-immune diseases, may well be the aetiological agent of these conditions and that anti-protozoal drugs may help by their action on these organisms.
The use of clotrimazole as an anti-fungal agent is known. Clotrimazole and related compounds for use as antimycotics is disclosed in U.S. Pat. No. 3,657,445 issued Apr. 18, 1972, to Buchel, et al. The use of clotrimazole is also described in the Sept. 12, 1975 issue (volume 17, No. 19) pages 77 to 78 of The Medical Letter published by The Medical Letter, Inc., 56 Harrison St., New Rochelle, N.Y. It has also been suggested to use nitroimidazole in the treatment of rheumatoid arthritis in the Journal of Tropical Medicine and Hygiene (vol 75) pages 64 to 66, Mar. 1972. It is believed that the nitro group in the imidazole ring is related to metronidiazole which is not effective in the treatment of rheumatoid arthritis. It is believed that the use of anti-fungal agents with anti-protozoal activity in the successful treatment of rheumatoid arthritis was not known prior to my discovery. Dehydrocholic acid has found use as a bile substitute.